A Conversation With

David Newman, Ph.D.

Chief
Natural Products Branch

Please tell us about the Natural Products Branch (NPB) and your role as Chief.

The Natural Products Branch (NPB) is part of the Developmental Therapeutics Program (DTP) and I became Branch Chief in 2006 after working at DTP in various other roles, including a chemist in charge of marine and microbial collections from 1991 to 2004 and acting chief from January 2005 until appointed chief in 2006. DTP has an overarching goal to serve as a hub of resources and drug discovery and preclinical development for anti-cancer therapeutics. The DTP is the home of the NCI-60 Tumor Cell Line Screen, an in vitro cell line screen designed to screen up to 3,000 compounds per year for potential anticancer activity. The NPB serves as, among other things, a repository for plant, marine, and microbial organism extracts. These extracts are tested on the NCI-60 Tumor Cell Line screen. Extracts are also available to outside researchers for use in experimental trials. Researchers must sign a Materials Transfer Agreement with NCI and will then have access to several available resources of samples through the NCI Natural Products Repository (Open Repository; Active Repository Program).
The DTP, of which NPB is part of, has a successful track record of chemotherapeutic agent development, including Paclitaxel (Taxol®), a compound originally extracted from the Pacific yew tree Taxus brevifolia. Can you speak about your program’s work with natural products?

The NPB set up a screening program similar to the one based on synthetic compounds, but using extracts of plants, microbes, and marine organisms back in the early 1960s. In the early days of NPB, we had academic groups that did the extractions, and subsequent chemistry. We had contractor research groups do in vivo mouse assays in those days. We also had a long-time arrangement with the USDA’s Economic Botany Group in Beltsville, Maryland and from these NCI screening efforts and partnerships came Paclitaxel, but those collaborations ceased in 1981.

By 1986, Dr. Michael Boyd (who was Associate Director of DTP at that time), had completely revised the screening system and instead of using animals and murine cell lines in the first tests, he set up a screen looking at 60 human cancer cell lines, which is now the NCI 60 Tumor Cell Line Screen. It was around then that we realized the flaws in the original NPB collection program. The first was "collections of opportunity" of the plants and other sources of samples. If someone was traveling somewhere in the world, they collected some plant or marine/microbial materials, but it meant that frequently they didn’t get a representative sample. Sometimes, particularly in the case of microbes, they didn’t even know what the sample was. So instead, we then set up the program to include collection contracts, where we competitively hired microbiologists, botanists, and marine biologists to do collections. We told the collectors, here are the resources go out and collect, and when you collect we want full details, such as the sample’s geographical coordinates, taxonomy, where it came from and when, together with enough material, usually a kilo dry weight for plants, and a kilo frozen wet weight for marine organisms. With this type of contract work, we were able to set up something we didn’t have before- a very large repository. We also set up the Natural Products Support Group (NPSG) lab at NCI-Frederick to process these materials in a consistent way.

The repository currently has a quarter of a million samples in it, including 160,000 plants, around 35,000 marine samples, and the rest are microbes. These are now made available to anyone in the world who signs a cooperative agreement. (See the Natural Products Repository links previously.)

We test extracts in the 60 cell line screen and we now test “active” extracts in animals directly. If it works in an animal where we’ve put a tumor, there is something in that extract that is worth following. You can’t do this in academia or industry; we can. When it comes to natural products per se, if someone brings something in or we obtain something, we do everything from the quality control up to producing the compound or arranging for its production usually in the source country or in the United States in conjunction with the source country. We do this with five people in NPB and a very talented group at the NCI Frederick National Laboratory for Cancer Research called the Natural Products Support Group (NPSG). The NPSG does everything from grinding and extraction, to providing the materials (both natural products and synthetic samples for the tumor cell screens ). Then if active, they follow up materials that are active in vivo,via chemical analyses of the “active” fractions following only the biologically active materials. However, nothing gets discarded as the materials found may well be active in another type of biological screen .

People always ask what the latest, greatest drug from the rainforest is and I always say Taxol®. There has not been a single compound drug, approved from the rainforest for any disease that I am aware of since Taxol® until very recently, as now we can include Synribo®, a natural product to treat cancer that was approved in October 2012 by the FDA. Homoharringtonine, which is the trivial name for the compound, was originally isolated from the seeds of Cephalotaxus harringtonia, which is a coniferous bush or small tree in the plum yew family. Homoharringtonine has really been around since the early 1960s from a USDA investigation with the earlier NPB. Since enough material could not be obtained for preclinical development by NPB in the middle 1960s, due to the source tree not being indigenous to the United States, the compound languished here but work was continued in the People’s Republic of China, where the source plant grew wild. The compound was in clinical trials in China for various leukemias, and was put into clinical trials in the United States in conjunction with NCI and a small company that ended up as part of TEVA Pharmaceuticals, following their recent purchase of Cephalon. It was finally approved as an anti-tumor drug, omacetaxine mepesuccinate (trade name, Synribo®), for the treatment of adults with chronic myelogenous leukemia (CML).

There are definitely significant discoveries made as a result of traditional medicine. And there will be more, but it may not necessarily be to treat an overarching disease like a specific type of cancer, it may be to treat related diseases or conditions, such as inflammation.

Has the NPB ever collaborated with OCCAM on any projects?

We have been working with OCCAM ever since your inception. And at this moment we are working with materials obtained with OCCAM through a Cooperative Agreement with Harvard University and a university in China (5U19CA128534-04) that is looking at Traditional Chinese Medicine (TCM) medicinal plants from China. This was a great agreement and it looked at 160 -200 TCM plants that were collected as they should be, following the Inner Canon
of Emperor Huangdi (Huang Di
Nei Jing). They were collected as described and control samples taken from elsewhere (the same plant, different areas). So with help from staff at OCCAM we were able to get those materials sent to us here at the NPB. We ended up with just under a metric ton of dried plant materials, all identified taxonomically, with the correct geographical sites. What we’ve done now is to take a small portion of each one, treat it the way we normally do and have it tested in our 60 cell line screen and we have seen some interesting activity. The next step is to have OCCAM scientists who are fluent in Mandarin go back and translate the traditional methodologies used for the preparation of this material in China. Our samples will be treated according to those methodologies. The traditional preparations may have been putting the plants in warm water, alkaline, acidic, or boiling water, even cold water, whatever the technique is. We will then assay those in the 60 cell line screen and this will give us an idea of whether the active potential of these samples comes from treating it one way or another. It will be interesting to see if there are similar results from the same plants taken from different areas. It will be the first time that I am aware of that there has been a thorough independent, blinded study of the medicinal plants.
What is one of the biggest challenges/issues in working with natural products?

One of the main issues is being certain of what you are working with. You’ll find that there are groups that claim American ginseng is good for a variety of things, and there very well may be some evidence there, but the fact is what they call American ginseng has half a dozen botanical variations. This comes back to my original comments: that you’ve got to be certain of what you have before you test it. It can be hard to determine what herbs and plants have been grown and tested under uncontrolled conditions, there may be info worth looking at, but trying to get that from the massive numbers of people claiming everything can be hard work.

Back to TCM, it has a 3000 year history and its components have some validity, because they have been tested for centuries, on everyone from the Emperors to farmers. However, you have to be sure what you are taking today is what was originally described. Modern day CAM practitioners and researchers are building upon 3000 years of information, although the information has been a selective interpretation, without going back and looking at the original sources. Hence the reason for doing the controls in our TCM experiments. We have to use materials that are from China, gathered, and prepared in the traditional methods.

One of the problems in the case of traditional medicines in cancer is there is no defined traditional medicinal use in cancers in the history. I use a very simple methodology, say we’ve got this material and the traditional literature says it works against this cancer. My first thought is always is it a cancer that can be recognized without a lab or surgery? Because in ancient times, there were no x-rays or sophisticated screening tests. Skin cancer you can see, some breast cancers may be detected without invasive screening techniques, but for the major cancers that have the highest mortality (lung, colon, pancreas, and prostate) there is no way — short of invasive analysis — to identify these cancer types. So when someone comes to me saying they have a traditional remedy that is used to treat pancreatic cancer, I am skeptical. The problem is that you can’t tell if the person really had cancer back in traditional times. So it is hard to take anecdotal or written histories of a TCM traditional drug that has been used for thousands of years and say it’s been used to treat cancer, because how did they know these people had cancer?

It comes down to a simple truth and I know that OCCAM and NCI in general believe in this too. I want to see evidence, scientific proof of the validity of the response, which means you have to know what you started with, and this is how good experimentation with natural products begins.
Do you have any advice to new investigators starting out in the natural products field?

My advice to them would be to go in with their eyes wide open. And to ask a very simple question, in the case of the disease that a natural product they are studying is purported to help: Is this a disease that can be diagnosed in the absence of a lab test or invasive techniques? If it can be, then start looking at it.

Also, in terms of what to get training in, you can get an awful lot of info from botany, but you need chemistry and pharmacology. This doesn’t mean to say you need a Ph.D. in each subject, but you need to specialize in one of them and have knowledge of the others. If you understand the botany, you know botanically it’s the correct material, that’s the first step. Pharmacologically, is there an effect? Chemically, how stable is it? What is it, what is in the mixtures? These are the questions you will deal with in your career in natural products whether investigating single agents as I do, or in the more complex mixtures as OCCAM, the NIH Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine do.